Nab-paclitaxel and Carboplatin Followed by Response-Based Local Therapy in Treating Patients With Stage III or IV HPV-Related Oropharyngeal Cancer (OPTIMA)

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This phase II trial studies nab-paclitaxel (paclitaxel albumin-stabilized nanoparticle formulation) and carboplatin followed by response-based local therapy in treating patients with stage III or IV human papillomavirus (HPV)-related oropharyngeal cancer. Drugs used in chemotherapy, such as paclitaxel albumin-stabilized nanoparticle formulation, carboplatin, hydroxyurea, fluorouracil, paclitaxel, and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them spreading. Radiation therapy uses high energy x rays to kill tumor cells. Giving nab-paclitaxel and carboplatin before chemoradiation may make the tumor smaller and reduce the amount of chemotherapy and radiation therapy needed. Assigning chemotherapy and radiation therapy based on response (response-based therapy) and giving patients who are responding well lower doses of treatment may help reduce the occurrence of side effects.

VI. To determine the rates of late toxicity with chemoradiation following surgery as determined by xerostomia, dental decay, osteroradionecrosis, G-tube dependency, tracheostomy placement and dysphagia.

VIII. 2-year PFS in patients treated on the Low-Risk, Intermediate-Risk Arm, and High-Risk Arms - early and late toxicities.

IX. Evaluate need for post radiotherapy/chemoradiotherapy (RT/CRT) surgery on low- and intermediate-risk arms based on response from induction chemotherapy.

X. Evaluate in a descriptive manner the role of transoral robotic surgery (TORS) resection/lymph node dissection (LND) when integrated into a de-escalation trial.

TERTIARY OBJECTIVES:

I. To evaluate pathologic/histologic appearance of tumor after induction chemotherapy and after CRT.

II. Translational research on blood and tissue samples. III. To profile tumors genetically and immunologically in order to assess in a descriptive manner genetic or immunological features characteristic of clinical behavior.

OUTLINE:

INDUCTION CHEMOTHERAPY: All patients receive paclitaxel albumin-stabilized nanoparticle formulation intravenously (IV) over 60 minutes on days 1, 8, and 15 and carboplatin IV over 30-60 minutes on day 1. Treatment repeats every 21 days for 3 courses in the absence of disease progression or unacceptable toxicity.

Patients are then assigned to 1 of 3 treatment groups based on response to induction chemotherapy.

GROUP A (LOW-DOSE ARM): Patients undergo radiation therapy once daily for 5 weeks.

GROUP B (INTERMEDIATE-DOSE ARM): Patients receive hydroxyurea orally (PO) twice daily (BID) on days 0-5, fluorouracil IV continuously on days 1-5, and paclitaxel IV over 60 minutes on day 1. Patients also receive low-dose radiation therapy BID on days 1-5. Treatment repeats every 14 days for 3 courses in the absence of disease progression or unacceptable toxicity.

GROUP C (STANDARD-DOSE ARM): Patients receive hydroxyurea PO BID on days 0-5, fluorouracil IV continuously on days 1-5, and paclitaxel IV over 60 minutes on day 1. Patients also receive standard-dose radiation therapy BID on days 1-5. Treatment repeats every 14 days for up to 5 courses in the absence of disease progression or unacceptable toxicity.*

*NOTE: At the discretion of the principal investigator (PI), patients may receive cisplatin IV over 1-3 hours every 3 weeks during radiation therapy instead of paclitaxel and undergo daily radiation therapy.

After completion of study treatment, patients are followed up for 30 days, every 3 months for 1 year, every 6 months for 2 years, and then annually for 2 years.

Patients receive hydroxyurea PO BID on days 0-5, fluorouracil IV continuously on days 1-5, and paclitaxel IV over 60 minutes on day 1. Patients also receive low-dose radiation therapy BID on days 1-5. Treatment repeats every 14 days for 3 courses in the absence of disease progression or unacceptable toxicity.

Drug: paclitaxel albumin-stabilized nanoparticle formulation

Given IV

Other Names:

ABI-007

nab paclitaxel

nab-paclitaxel

nanoparticle albumin-bound paclitaxel

Drug: carboplatin

Given IV

Other Names:

Carboplat

CBDCA

JM-8

Paraplat

Paraplatin

Radiation: radiation therapy

Undergo radiation therapy

Other Names:

irradiation

radiotherapy

therapy, radiation

Drug: paclitaxel

Given IV

Other Names:

Anzatax

Asotax

TAX

Taxol

Drug: fluorouracil

Given IV

Other Names:

5-fluorouracil

5-Fluracil

5-FU

Drug: hydroxyurea

Given PO

Other Names:

HU

HYD

Hydrea

Hydroxycarbamide

Hydurea

Other: laboratory biomarker analysis

Correlative studies

Procedure: quality-of-life assessment

Ancillary studies

Other Name: quality of life assessment

Experimental: Group C (combination chemotherapy, high-dose radiation)

Patients receive hydroxyurea PO BID on days 0-5, fluorouracil IV continuously on days 1-5, and paclitaxel IV over 60 minutes on day 1. Patients also receive standard-dose radiation therapy BID on days 1-5. Treatment repeats every 14 days for up to 5 courses in the absence of disease progression or unacceptable toxicity.*

*NOTE: At the discretion of the PI, patients may receive cisplatin IV over 1-3 hours every 3 weeks during radiation therapy instead of paclitaxel and undergo daily radiation therapy.

PFS, evaluated using RECIST version (v) 1.1 [ Time Frame: Time from enrollment until disease progression or death from any cause, assessed at 2 years ]

If all patients are followed for two years, the PFS rate and confidence interval will be determined based on the exact binomial distribution. Otherwise PFS will be estimated using the Kaplan-Meier method and a (large-sample) one-sided 90% confidence interval will be derived for the PFS rate at two years to test the non-inferiority hypothesis. Median PFS will be estimated as described in Brookmeyer and Crowley.

Secondary Outcome Measures :

Rate of pathologic complete response on post treatment biopsy/surgery, evaluated using RECIST v1.1 [ Time Frame: Up to 8 weeks after completion of CRT ]

Pathologic response rates will be determined and 95% confidence intervals obtained using the exact binomial distribution.

Clinical complete response by positron emission tomography, evaluated using RECIST v1.1 [ Time Frame: Up to 5 years ]

Clinical response rates will be determined and 95% confidence intervals obtained using the exact binomial distribution.

Overall survival [ Time Frame: From the date of registration to the date of death or date of last patient contact if censored, assessed up to 5 years ]

Kaplan-Meier curves will be generated. In addition, cumulative incidence curves will be derived for the competing risks of cancer and non-cancer death.

Cancer-specific survival [ Time Frame: Up to 5 years ]

Kaplan-Meier curves will be generated. Patients dying from non-cancer related causes will be censored at the time of death. In addition, cumulative incidence curves will be derived for the competing risks of cancer and non-cancer death.

Rates of acute toxicity, determined by incidence of mucositis, xerostomia, anorexia, weight loss, dermatitis and G-tube placement [ Time Frame: Up to 5 years ]

Toxicity rates will be summarized by type of toxicity, grade, and attribution. The incidence of acute (mucositis, xerostomia, anorexia, weight loss, dermatitis and G-tube placement) toxicities will be estimated along with 95% confidence intervals.

Rates of late toxicity, determined by incidence of xerostomia, dental decay, osteroradionecrosis, G-tube dependency, tracheostomy placement and dysphagia [ Time Frame: Up to 5 years ]

Toxicity rates will be summarized by type of toxicity, grade, and attribution. The incidence of late-term (xerostomia, dental decay, osteroradionecrosis, G-tube dependency, speech abnormalities, tracheostomy placement and dysphagia) toxicities will be estimated along with 95% confidence intervals.

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HPV testing using an E6/E7 based assay is preferred, and does not require any validation (e.g. HPV in situ hybridization [ISH] or HPV E6/E7 polymerase chain reaction [PCR])

For oropharyngeal tumors p16 immunohistochemistry (IHC) positivity is sufficient to enroll and initiate treatment (p16 IHC interpretation to follow guidelines by Jordan/Lingen et al 2012); it is recommended that p16 IHC positivity is validated at a later point (during or after treatment) using an E6/E7 based test at the University of Chicago and provided slides will be used

For non-operative (OP) tumors accurate HPV testing (i.e. ISH, or E6/E7 based testing) is required for enrollment and treatment initiation

The primary and nodal involvement must be assessable on clinical exam (mucosal and lymph node exam)

The primary and nodal involvement must have been defined bi- or uni-dimensional measurements measurable by RECIST

No previous radiation or chemotherapy for a head and neck cancer

No surgical resection for a head and neck cancer within 8 weeks of enrollment (although lymph node biopsy including excision of an individual node with presence of residual nodal disease, or surgical biopsy of the tumor is acceptable)

Pregnant and nursing women are excluded; men and women of child-bearing potential are eligible but must consent to using effective contraception during therapy and for at least 3 months after completing therapy; women with child-bearing potential must have a negative serum or urine beta-human chorionic gonadotropin (B-hCG) pregnancy test at screening

Other coexisting malignancies or malignancies diagnosed within the previous 3 years no evidence of disease for at least 3 years; exceptions to this include non-melanoma skin cancer, cervical cancer in situ, well differentiated thyroid cancer or prostate cancer; other cancers that per assessment of the PI are not prognosis limiting can be allowed after review by the PI

Prior surgical therapy other than incisional or excisional biopsy and organ-sparing procedures such as debulking of airway-compromising tumors or neck dissection in a patient with an unknown primary tumor; residual tumor is required for enrollment on study